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Wednesday, 25 November 2015 10:11

## Ensuring thermodynamic stability of amorphous solid dispersions by predicting drug-polymer solubility

The potential of amorphous solid dispersions to improve the solubility, dissolution rate and bioavailability of poorly water soluble drugs is well known. However, the number of formulations that have made it through to the market is limited because of the unstable nature of the amorphous form, which often results in recrystallization of the drug with the subsequent loss of the solubility and dissolution advantages. Thus, ensuring the stability constitutes a major challenge in the development of amorphous solid dispersions.

Published in Research Highlights
Wednesday, 17 June 2015 14:00

We have developed a new technique to better understand what happens to the microstructure inside a tablet during rapid disintegration.

Published in Research Highlights
Thursday, 11 September 2014 00:00

# Background

The mechanism of plastic deformation in amorphous polymers is still obscure due to lack of experimental techniques to probe molecular mobility during active deformation. Lee et al. showed an increase in a segmental mobility by several decades using a specific active deformation protocol (uniaxial tensile creep) by directly measuring the molecular mobility using an optical photobleaching approach [1]. Our previous studies using ATR-FTIR spectroscopy showed that compression of amorphous solid dispersions containing naproxen and PVP or PVP-VA appeared to affect the drug-polymer interactions, the drug-polymer mixing and the physical stability of the system [2, 3]. Deformation can affect the molecular dynamics of amorphous polymers that include local bonds, segmental and whole chain mobility. It potentially leads to conformational changes and also enhances or affects local bond motions of polymers which may be involved in intermolecular interactions with drugs in solid dispersions. The objective of this study is to understand the effect of compression on the local and segmental mobility of PVP-VA to understand the molecular origin of the differences in drug-polymer interactions between the compressed and the uncompressed solid dispersions. The impact of pharmaceutical tabletting on the molecular dynamics of amorphous solid dispersions can be critical in terms of physical stability of the drug during storage.

# Methods

High resolution broadband dielectric spectroscopy (ALPHA Analyzer, Novocontrol Technologies) was used to measure the complex dielectric responses (Eqn. \ref{eq:1}, ε' and ε'' are the real and the imaginary part) of the compressed (565 MPa) (comp), the slightly compressed (scomp) and the powder (pow) PVP-VA 64 and powder PVP K25 samples in the frequency range from 10-1 to 106 Hz.

$$\varepsilon (\omega)=\varepsilon' (\omega) - i\varepsilon'' (\omega)\label{eq:1}$$

The “conduction free” dielectric loss was computed from the real part of the dielectric spectra using the Kramers-Kronig relation to suppress the Ohmic conduction interference in the imaginary part of the dielectric response (Eqn. \ref{eq:2}) [4].

$$\varepsilon'' (\omega_0)=\frac{\sigma_{dc}}{\varepsilon_\nu\omega_0}+\frac{2}{\pi}\int_0^\inf \varepsilon'(\omega)\frac{\omega_0}{\omega^2-\omega_0^2}\text{d}\omega\label{eq:2}$$

Generally, the activation energy according to the Arrhenius-law is usually considered a true energetic barrier, however, processes that involve cooperativity might additionally show an entropic “barrier”. The Starkweather analysis allows to separate the activation energy into its enthalpic and entropic part to assess the cooperative nature of the secondary relaxation of PVP-VA (Eqns. \ref{eq:3} and \ref{eq:4}) (for the details of the equations refer to [5]).

$$f=\frac{k_B T}{2\pi h}\exp \left( -\frac{\Delta H^{\ddagger}}{RT} \right)\exp\left(\frac{\Delta S^{\ddagger}}{R} \right)\label{eq:3}$$

$$E^{*}_{a}=RT\left( 1+ \ln \frac{k_B}{2\pi h} \ln \frac{T}{f} \right)\label{eq:4}$$

# Results and Discussion

The secondary relaxation of compressed PVP-VA shifts synchronously with the primary relaxation to lower temperature compared to the powder and slightly compressed samples even after annealing in the supercooled liquid state (Fig. 1). The source of the secondary relaxation process is likely originating from the vinyl pyrrolidone moiety of PVP-VA. Thus, compression appeared to enhance the localised motion which likely originates from the conformational transition involving the N-C(H) bond in PVP-VA and also the segmental mobility due to dynamic Tg [6].

The non-zero activation entropy of compressed PVP-VA was higher than the powder sample which indicates the presence of a higher entropic barrier during conformational reorientation for the compressed sample (Table 1). Moreover, it may also indicate a higher cooperative nature of the β relaxation process for the compressed sample as the result of enhanced conformational rotations.

The primary relaxation process starts at a very low temperature for the compressed PVP-VA and an additional wing was also identified with a mean relaxation time smaller than the powder and the slightly compressed PVP-VA (Fig. 2).

# Conclusion and Outlook

The molecular dynamics results support the idea that severe compression affects the local and the segmental mobility of PVP-VA. Compression of PVP-VA appeared to lead to a shorter time scale for the secondary (β) relaxation process. Moreover, the primary relaxation process starts at a very low temperature for the compressed PVP-VA and an additional wing was also identified with a mean relaxation time smaller than the powder and the slightly compressed PVP-VA due to the heterogeneity in segmental mobility imparted by compression. The observation can be very useful for drug containing amorphous solid dispersions which are stabilised by specific drug-polymer interactions. The current study on PVP-VA should also be extended to one with binary solid dispersions stabilised by a strong and a weak drug-polymer hydrogen bonding further to probe the effect of compression in the molecular dynamics of both the drug, the polymer and their specific interactions.

# References

[1]    Lee, H. N.; Paeng, K.; Swallen, S. F.; Ediger, M. Science 2009, 323, 231.
[2]    Ayenew, Z.; Paudel, A.; Van den Mooter, G. Eur. J. Pharm. Biopharm. 2012, 81, 207.
[3]    Worku, Z. A.; Aarts, J.; Van den Mooter, G. Mol. Pharmaceutics 2014, 11, 1102.
[4]    Wübbenhorst, M.; van Turnhout, J. J. Non-Cryst. Solids 2002, 305, 40.
[5]    Starkweather Jr, H. W. Polymer 1991, 32, 2443.
[6]    Tonelli, A. Polymer 1982, 23, 676.

# PSSRC Facilities

The Research group of Prof. Guy Van den Mooter focuses on the study of the physical chemistry of solid (molecular) dispersions prepared by hot melt extrusion, spray drying, bead coating and spray congealing. It is the aim to correlate the physical structure of the drug-polymer dispersions to their pharmaceutical performance and stability profile, and to correlate formulation and processing parameters to the resulting physical structure. Analytical techniques such as thermal analysis (DSC, MTDSC, TGA, hot-stage microscopy, isothermal microcalorimetry, solution calorimetry), X-ray powder diffraction, infrared spectroscopy, solid state NMR, broadband dielectric spectroscopy and in vitro (intrinsic) dissolution testing are being used for this purpose. Other (solid state) analytical techniques that are available are (powder) rheology, He-pycnometry, instrumented compression testing, SEM, TEM, coulter counter and Laser diffraction.

As part of the Center for Drug Delivery and Analysis of KU Leuven, this research group is also involved in formulation development and preformulation studies (a.o. study of polymorphism) for pharmaceutical companies.

Published in Research Highlights
Wednesday, 02 July 2014 00:00

## Nanocrystals - from fast dissolution and improved solubility to controlled release applications

Problems related to low oral bioavailability due to poor solubility of new drug candidates are an increasing challenge in pharmaceutical research and formulation development. One efficient way to improve solubility is the utilization of nanocrystallization techniques: pharmaceutical nanocrystals are solid drug particles covered by a stabilizer layer with approximated size typically between 100 and 500 nm. Nanocrystal studies have been conducted since the beginning of the 1990’s and the first product entered the market after 10 years of intensive research. At first, nanocrystals were utilized purely for improved dissolution, but today also controlled release applications are in use.

Published in Research Highlights
Friday, 15 November 2013 15:55

# Introduction

Following the implantation of European regulation with respect to medicinal products for paediatric use, scientist community has to speed up for making medicine available for children by encountering multiple problems of paediatric formulation [1]. Indeed, the taste of oral medicine is one of the most crucial factors influencing adherence to therapeutic regimens and therapeutic outcomes [2].

Published in Research Highlights
Saturday, 07 September 2013 08:01

# Background

Solid dispersions are an intensively investigated enabling technology to formulate poorly soluble drugs. Many contributions already studied their higher solubility and resulting dissolution rate as well as the challenges at the level of physical stability due to their high intrinsic energy. Whereas the vast majority of these studies focus on the bulk characteristics of the samples, we are convinced that the (often distinct) properties of the sample surface should not be overlooked.

Published in Research Highlights
Wednesday, 03 July 2013 09:16

# Background

The structural and physical stability of solid dispersions have not been adequately explored during post spray drying manufacturing processes. Solid dispersions are preferentially formulated as solid dosage forms such as tablets and capsules. Formulation parameters of spray drying may lead to differences in physical form and amorphous content of solids in single component systems [1]. However, there is limited understanding on the effect of spray drying processes and formulation variables on drug-polymer mixing in solid dispersions and this limitation also extends to the unit operations such as milling and tabletting. The drug-polymer mixing in solid dispersions was evaluated in two different laboratory spray dryers, the Buchi-mini spray dryer and Pro-C-epT Micro spray dryer (Figure 1). The effect of compression on the structural and the physical stability of the spray dried solid dispersions was investigated as a major scope of this study.

Published in Research Highlights
Wednesday, 19 June 2013 09:39

# Non-linear Optical Imaging

Non-linear optical imaging is an emerging technique for imaging drugs and dosage forms [1]. Non-linear optical imaging may be used for non-destructive, non-contact imaging of solid drugs and dosage forms. It offers chemical and structural specificity with no requirement for labels, sub-micron spatial resolution (inherent confocal nature), rapid video-rate image acquisition, and the ability to image samples in aqueous environments in situ.

These combined features make non-linear optical imaging unique compared to existing imaging approaches in the pharmaceutical setting and make the technique well suited to a wide range of solid-state formulation and drug delivery analyses. These include imaging chemical and solid-state form distributions in dosage forms, drug release and dosage form digestion, and drug and micro/nanoparticle distribution in tissues and within live cells. While non-linear optical imaging is comparatively well established in the biomedical field, pharmaceutical applications of non-linear optical imaging are much less widely explored.

Published in Research Highlights
Monday, 15 April 2013 10:28

# Introduction

Continuous processing is a promising approach for solid dosage manufacturing. High-shear wet granulation is performed in continuous mode using twin screw granulators (TSG), characterized by a modular screw profile including a sequence of different screw elements with various shapes, orientation and functions. For process engineers it is a challenge to come up with prediction models to establish the relationship between equipment and material attributes, process data and the end-product testing results. If a reliable model is available which is able to predict the quality of the product, it can be inverted to obtain the design space, corresponding to that set of operating conditions required for achieving the target product quality (Figure 1). Such a modelling framework combined with in-process measurements, can provide a good mechanistic insight into the important parameters of continuous

Published in Research Highlights
Tuesday, 02 April 2013 14:43

# Introduction

Oral films have gained interest in the last couple of years. Films for oral application offer an interesting new approach for drug administration. Active pharmaceutical ingredients (API) can be implemented in thin-sheeted polymer film matrices. These dosage forms are intended to be placed in mouth to dissolve in the saliva without the need of additional liquid and without swallowing of a solid dosage form.

Published in Research Highlights
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